The antibiotic adriamycin is widely used clinically in the management of leukemias and the treatment of various solid tumors. The major toxic reactions associated with its use include suppression of bone marrow activity, gastrointestinal disturbances, alopecia, stomatitis, and delayed cardiotoxicity leading to irreversible congestive heart failure. Adriamycin analogs and derivatives with improved therapeutic efficacy, extended spectrum of antitumor activity, or less toxicity than the parent agent are therefore of immediate clinical importance and relevance. These drug advantages are all exhibited by N-trifluoroacetyladriamycin-14-valerate (AD 32), an adriamycin analog first prepared and developed in these laboratories and now in phase II clinical trial. Studies related to AD 32 continue, with respect to analysis of structure-activity correlates and to the development of "second-generation" AD 32 analogs with improved water solubility. A variety of other semisynthetic modifications continue to be investigated, including both chromophore-modified analogs and modification of the naturally occurring glycoside moiety. In the latter category are included analogs bearing "fraudulent" glycosides. Target compounds are evaluated for biological activity in vitro (cell growth inhibition and DNA-binding studies) and in vivo (murine antitumor assays) on an ongoing basis. The advantages of AD 32 over adriamycin experimentally and clinically clearly continue to justify the search for additional analogs with even greater therapeutic potential.